Ichthyosis vulgaris (IV; OMIM#146700) is the most common inherited disorder of keratinisation and one of the most frequent single gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6051 healthy English schoolchildren1.
The phenotypic characteristics of IV include palmar hyperlinearity, keratosis pilaris and a fine scale most markedly seen over the lower abdomen, arms and legs2. Filaggrin (filament aggregating protein) is important in the formation of the stratum corneum3-5. Keratohyalin granules in the granular layer of interfollicular epidermis are predominantly composed of the 400 kDa protein profilaggrin. Following a short, unique N-terminal domain, most of the profilaggrin molecule consists of 10-12 repeats of the 324 amino acid filaggrin sequence6. Upon terminal differentiation of granular cells, profilaggrin is proteolytically cleaved into ˜37 kDa filaggrin peptides and the N-terminal domain containing an S100-like calcium binding domain. Filaggrin rapidly aggregates the keratin cytoskeleton, causing collapse of the granular cells into flattened anuclear squames. This condensed cytoskeleton is cross-linked by transglutaminases during formation of the cornified cell envelope (CCE). The CCE is the outermost barrier layer of the skin which not only prevents water loss but also impedes the entry of allergens and infectious agents7. Filaggrin is therefore a key protein in facilitating epidermal differentiation and maintaining barrier function.
Immunoblotting studies have shown that filaggrin protein was absent or markedly reduced in IV patients' skin and/or keratinocytes8-10. In addition, decreased filaggrin mRNA has been demonstrated in some individuals with IV11. A recessive mouse mutant, flaky tail (ft), bears the histological and ultrastructural hallmarks of human IV12 and strong genetic linkage has been obtained to the murine filaggrin locus (FLG)13,14. Although biochemical analysis has shown defective profilaggrin processing in ft/ft homozygotes12, any genomic mutation in the FLG gene has not hitherto been identified.
It is amongst the objects of the present invention to provide a method of diagnosing ichthyosis vulgaris and atopic diseases or predisposition thereto.